Background and Health Relatedness: Narcolepsy is a disease that causes excessive sleepiness and abnormal regulation of REM sleep. The condition is chronic, debilitating, and detracts from quality of life. It is linked to a defect in the hypocretin (orexin) neurotransmission system in humans, dogs with hereditary disease, and mice. The cause of human narcolepsy is unknown. Human narcolepsy is associated with HLA DQB1*0602, is rarely familial, and has been associated with a mutation in only one case to date. Hypotheses: 1) HLA DQB 1 *061J2 positive humans with narcolepsy have serum and/or CSF antibodies reactive to one or more of the five components of the hypocretin neurotransmission system or hypocretin secreting cells. 2) Immunizing rats with the components of the hypocretin neurotransmission system will produce experimental autoimmune narcolepsy, which will mimic human narcolepsy and the narcoleptic symptoms seen in other animal models for the disease. Specific Aims: 1) Use ELISAs and IPAs to study the sera and CSF of HLA DQB1*0602 positive narcolepsy patients with cataplexy (including child and ethnically and gender diverse samples) to find antibodies reactive with preprohypocretin, hypocretin 1 and 2, and hypocretin receptor 1 and 2. Conduct Western blots and immunofluorescence studies with serum and CSF samples to determine antibody reactivity to cadaveric normal hypothalamus (known to be rich in the five known components of the hypocretin system) and transfected HEK 293 cells expressing the known components of the hypocretin neurotransmission system. Positive sera and CSF will also be preadsorbed and the studies will be repeated to determine if antibody specificity for these proteins exists. Results will be correlated between CSF and serum and epitope mapping will be done using positive sera. 2) Establish an experimental autoimmune animal model for narcolepsy by actively immunizing rats with recombinant preprohypocretin and hypocretin receptor 1 and 2 protein and by immunizing rats with plain and KHL-conjugated synthetic hypocretin system proteins and peptides. Passively immunized rats using polyclonal antibodies and purified antibodies will similarly be studied. Long term objectives: This translational, multidisciplinary research will demonstrate fundamental insights into the cause of narcolepsy and will open avenues for new interventions and preventative measures for this debilitating disease.